This invention relates to pyrimidine compounds and pharmaceutically acceptable salts, solvates and prodrugs thereof. The present compounds have been found useful as antitumor and antiangiogenic agents. Methods using these compounds are also provided.
Angiogenesis, the formation of new blood vessels, occurs during development and in normal adults during wound healing, pregnancy, and corpus luteum formation. Although angiogenesis is limited in normal adults, it is induced in many disease states including cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, and restenosis (reviewed in Folkman, 1995).
Tumors require angiogenesis to grow beyond 1-2 mm3. (Folkman, 1990). The increased blood flow to the tumor allows for continued growth as well as metastasis because successful metastasis requires the presence of blood vessels to allow for the tumor cells to enter the circulation. The close interplay between angiogenesis and metastasis contributes to the poor prognosis seen in patients with highly angiogenic tumors. Cherrington et al., 2000.
Some of the most well characterized regulators of angiogenesis are growth factors and receptor tyrosine kinases (RTKs) involved in the migration and proliferation of endothelial cells. Of primary interest for angiogenesis are Flt-1 and Flk-1/KDR, the receptors for vascular endothelial growth factor (VEGF), as well as Tie 1 and Tie 2/Tek, the receptors for angiopoietins. These four receptors are expressed primarily on endothelial cells and play a direct role in angiogenesis. Additional RTKs with broader expression patterns implicated in angiogenesis are platelet-derived growth factor receptors (PDGFRs); fibroblast growth factor receptors (FGFRs); the hepatocyte growth factor/scatter factor (HGF/SF) receptor, Met; and epidermal growth factor receptors (EGFRs), although it is thought that the EGFR is likely to act predominantly in directly driving the growth of tumor cells rather than through angiogenesis. Cherington et al., 2000.
VEGF is a dimeric protein also known as vascular permeability factor because it acts on endothelial cells to regulate permeability of those cells as well as their proliferation. These two activities are mediated through its tyrosine kinase receptors, VEGFR1/Flt-1 and VEGFR2/Flk-1/KDR (KDR is the human homologue of Flk-1). VEGF and its receptors are expressed in angiogenic tissues during development, wound healing and other situations when angiogenesis occurs. The role of VEGF in tumor angiogenesis has also been clearly demonstrated using tumor models in rodents (reviewed in Hanahan, 1997; Shawver et al., 1997); there is an extensive literature exists linking VEGF with human cancers such as pulmonary adenocarcinoma (Takanami et al., 1997) and non-small cell carcinoma (NSCLC) (Fontanini et al., 1999; Takahama et al., 1998; Ohta et al., 1996). Survival of patients with VEGF-positive tumors was significantly less than patients with VEGF-negative tumors. For example, in one study of non-small cell carcinoma (NSCLC), patients with low VEGF levels had a median survival time of 151 months, whereas those with high VEGF expression had a mean survival time of only 8 months. Ohta et al., 1996.
VEGF and its receptors, in particular, serve as excellent targets for anti-angiogenesis therapy because KDR is an endothelial cell-specific VEGF receptor expressed primarily during the angiogenic process. The VEGF signaling cascade has been validated as a target for therapeutic intervention by several methods. See, e.g., Saleh et al., 1996, Claffey et al., 1996, Kim et al., 1993 and Asano et al., 1995.
Epidermal growth factor (EGF) is one of several naturally occurring proteins that promotes normal cell proliferation in a tightly regulated manner by binding to its receptor, EGFR, and sending growth signals via the receptor tyrosine kinase enzyme activity to the nucleus of the cell and thus controlling growth. In many human cancers, EGFR is either overexpressed or mutated, leading to aberrant signaling and the development of a tumor; thus inhibition of EGF receptor kinase is also a target in anti-tumor therapy.
Many pyrimidine systems have been studied for their ability to inhibit growth of tumors, through inhibition of angiogenesis and/or inhibition of cell growth, by targeting receptor tyrosine kinases. See, for example, Sun, Li and McMahon, G. xe2x80x9cInhibition of tumor angiogenesis by Synthetic Receptor Tyrosine Kinase Inhibitorsxe2x80x9d. Drug Discov Today 2000, 5 (8): 344-353, and Traxler, P. and Furet, P., xe2x80x9cStrategies toward the Design of Novel and Selective Protein Tyrosine Kinase Inhibitorsxe2x80x9d Pharmacol. Ther. 1999 82 (2-3): 195-206, which disclose synthetic pyrimidine compounds which have been shown to be effective TK inhibitors.
Pyrimidine systems have also been shown to inhibit dihydrofolate reductase (DHFR) enzyme activity. Because DHFR reduces dihydrofolate to tetrahydrofolate, inhibition of DHFR deprives the cell of tetrahydrofolate, without which the cell cannot produce 5,10-methylene-tetrahydrofolate, essential for cell growth. The inhibition of DHFR results in the inhibition of DNA synthesis and leads to cell death.
Additionally, some pyrimidine derivatives are known to function as thymidylate synthase (TS) inhibitors. TS, along with DHFR, forms part of the system responsible for the synthesis of deoxythymidylate (dTMP) from deoxyuridylate (dUMP). TS catalyzes the sole de novo synthesis of dTMP from dUMP. Inhibition of TS, therefore, deprives the cell of thymidine, which is an essential constituent of DNA.
In general, it is highly desirable to develop new antiangiogenic compounds which inhibit formation of new blood vessels and development of a new blood supply, as these can selectively target various tumor types and prevent growth of circulation in the tumor and inhibit metastasis. Because angiogenesis is limited in healthy adults, compounds which inhibit angiogenesis can selectively target tumors as compared with other compounds and anti-cancer agents using other modes of action, which often indiscriminately act on tumor and healthy cells alike. There is a need for compounds which provide the desired enzyme inhibition with a high degree of selectivity and low toxicity.
The present invention provides pyrimidine compounds, and pharmaceutically acceptable salts, solvates and prodrugs thereof, having the formula (1): 
where X, X1, X2, X3 and X4 are from one to about three atoms, are the same or different and are independently selected from the group consisting of hydrogen, an alkyl group, a alkenyl group, an heteroalkyl group and an heteroalkenyl group,
and any carbons or nitrogens of said alkyl group, alkenyl group, heteroalkyl group or heteroalkenyl group can optionally be substituted with a straight, branched or cyclic lower alkyl group of from 1 to about 6 carbons;
Z is selected from the group consisting of C, CH, CH2, N, NH, S, O, CHxe2x95x90CH, CHxe2x95x90N and Nxe2x95x90CH;
L is selected from the group consisting of C, CH, CH2, N, NH, S, O, CHxe2x95x90CH, CHxe2x95x90N and Nxe2x95x90CH, but when Z is C, CH, CHxe2x95x90CH or CH2 then L is N, NH, S or O;
M is selected from the group consisting of carbon and CH;
the chemical bond between L and M is selected from the group consisting of a single bond and a double bond, and M is carbon when the bond is a double bond, and M is CH when the bond is a single bond;
the chemical bond between M and Z is selected from the group consisting of a single bond and a double bond, and M is carbon when the bond is a double bond, and M is CH when the bond is a single bond;
but when the bond between L and M is a double bond the bond between M and Z is a single bond;
at least one of R2, R3, R4, or R5 is present;
R1, R4 and R5 are the same or different and are selected from the group consisting of hydrogen, an alicyclic group, a heterocyclic group, an aryl group, a heteroaryl group, an alkylaryl group, a alkylheteroaryl group, a substituted aryl group, a substituted heteroaryl group, a substituted alkylaryl group and a substituted alkylheteroaryl group;
R2 and R4 are optional, are the same or different and are selected from the group consisting of hydrogen, an alicyclic group, a heterocyclic group, an aryl group, a heteroaryl group, an alkylaryl group, a alkylheteroaryl group, a substituted aryl group, a substituted heteroaryl group, a substituted alkylaryl group, a substituted alkylheteroaryl group, and p-aroyl-glutamate;
and each substituent of any substituted group is the same or different and is selected from the group consisting of a straight, branched or cyclic lower alkyl, alkenyl or alkynl group of from one to about 6 carbons, an group, an alkoxyaryloxy group, and a halogen.
In one aspect of the present invention, these pyrimidine compounds can function as receptor tyrosine kinase inhibitors, and prevent the development of new blood vessels in tumors. Specifically, these compounds have been found to inhibit several receptor tyrosine kinases, including vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and platelet derived growth factor (PDGF) receptor tyrosine kinases. Thus, the compounds of the present invention are dual acting in that they can inhibit angiogenesis by inhibiting tyrosine kinases directly involved in angiogenesis, (such as by inhibiting the VEGF receptor tyrosine kinase), and inhibit receptor tyrosine kinases involved in cell growth, for example, by competitively binding to TK receptors such as the EGF receptor tyrosine kinase. These compounds have an antiangiogenic and an antitumor effect.
In an additional aspect of the present invention, certain of these pyrimidine compounds function as triple or quadruple acting agents. That is, they inhibit receptor tyrosine kinases, and they also inhibit DHFR and/or thymidylate synthase, thus further providing additional inhibition of tumor growth. Both the dual, triple and quadruple acting compounds are unique in their ability to provide multiple mechanisms of action in structurally distinct compounds. None of the existing compounds known to inhibit receptor tyrosine kinases are known to additionally inhibit DHFR and/or TS, nor do any have the distinct chemical structures described and claimed herein. It is thought that the compounds having less bulky substituents at the 4-position on the pyrimidine ring are able to provide the multiple mechanisms of action, although the inventor does not wish to be bound by this.
Methods for using these compounds in the treatment of various illnesses are also within the scope of the invention; for example, these compounds are useful for therapeutic and/or prophylactic purposes as antitumor or anti-angiogenic agents or to otherwise destroy or minimize growth or proliferation of cancerous cells in cancer patients or in the treatment of other illnesses.
It is an object of the present invention, therefore, to provide pyrimidine derivative compounds, and pharmaceutically acceptable salts and prodrugs thereof, having antitumor and/or anti-angiogenic activity.
It is an additional object of the present invention to provide pyrimidine compounds, and pharmaceutically acceptable salts and prodrugs thereof, for substantially inhibiting receptor tyrosine kinase(s) activity.
It is a further object of this invention to provide pyrimidine compounds, and pharmaceutically acceptable salts and prodrugs thereof, for substantially inhibiting receptor tyrosine kinases and/or dihydrofolate reductase and/or thymidylate synthase enzymes.
It is an additional object of this invention to provide a method of the present pyrimidine compounds and their derivatives to treat various illnesses such as cancer.
These and other aspects of the invention will be more fully understood from the following detailed description of the invention, the drawings and the claims appended hereto.